Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Cost-effectiveness of the National Health Service Abdominal Aortic Aneurysm Screening Programme in England.

BACKGROUND: Implementation of the National Health Service abdominal aortic aneurysm (AAA) screening programme (NAAASP) for men aged 65 years began in England in 2009. An important element of the evidence base supporting its introduction was the economic modelling of the long-term cost-effectiveness of screening, which was based mainly on 4-year follow-up data from the Multicentre Aneurysm Screening Study (MASS) randomized trial. Concern has been expressed about whether this conclusion of cost-effectiveness still holds, given the early performance parameters, particularly the lower prevalence of AAA observed in NAAASP. METHODS: The existing published model was adjusted and updated to reflect the current best evidence. It was recalibrated to mirror the 10-year follow-up data from MASS; the main cost parameters were re-estimated to reflect current practice; and more robust estimates of AAA growth and rupture rates from recent meta-analyses were incorporated, as were key parameters as observed in NAAASP (attendance rates, AAA prevalence and size distributions). RESULTS: The revised and updated model produced estimates of the long-term incremental cost-effectiveness of £5758 (95 per cent confidence interval £4285 to £7410) per life-year gained, or £7370 (£5467 to £9443) per quality-adjusted life-year (QALY) gained. CONCLUSION: Although the updated parameters, particularly the increased costs and lower AAA prevalence, have increased the cost per QALY, the latest modelling provides evidence that AAA screening as now being implemented in England is still highly cost-effective.

Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness.

BACKGROUND: Small abdominal aortic aneurysms (AAAs; 3.0-5.4 cm in diameter) are usually asymptomatic and managed by regular ultrasound surveillance until they grow to a diameter threshold (commonly 5.5 cm) at which surgical intervention is considered. The choice of appropriate surveillance intervals is governed by the growth and rupture rates of small AAAs, as well as their relative cost-effectiveness. OBJECTIVES: The aim of this series of studies was to inform the evidence base for small AAA surveillance strategies. This was achieved by literature review, collation and analysis of individual patient data, a focus group and health economic modelling. DATA SOURCES: We undertook systematic literature reviews of growth rates and rupture rates of small AAAs. The databases MEDLINE, EMBASE on OvidSP, Cochrane Central Register of Controlled Trials 2009 Issue 4, ClinicalTrials.gov, and controlled-trials.com were searched from inception up until the end of 2009. We also obtained individual data on 15,475 patients from 18 surveillance studies. REVIEW METHODS: Systematic reviews of publications identified 15 studies providing small AAA growth rates, and 14 studies with small AAA rupture rates, up to December 2009 (later updated to September 2012). We developed statistical methods to analyse individual surveillance data, including the effects of patient characteristics, to inform the choice of surveillance intervals and provide inputs for health economic modelling. We updated an existing health economic model of AAA screening to address the cost-effectiveness of different surveillance intervals. RESULTS: In the literature reviews, the mean growth rate was 2.3 mm/year and the reported rupture rates varied between 0 and 1.6 ruptures per 100 person-years. Growth rates increased markedly with aneurysm diameter, but insufficient detail was available to guide surveillance intervals. Based on individual surveillance data, for each 0.5-cm increase in AAA diameter, growth rates increased by about 0.5 mm/year and rupture rates doubled. To control the risk of exceeding 5.5 cm to below 10% in men, on average a 7-year surveillance interval is sufficient for a 3.0-cm aneurysm, whereas an 8-month interval is necessary for a 5.0-cm aneurysm. To control the risk of rupture to below 1%, the corresponding estimated surveillance intervals are 9 years and 17 months. Average growth rates were higher in smokers (by 0.35 mm/year) and lower in patients with diabetes (by 0.51 mm/year). Rupture rates were almost fourfold higher in women than men, doubled in current smokers and increased with higher blood pressure. Increasing the surveillance interval from 1 to 2 years for the smallest aneurysms (3.0-4.4 cm) decreased costs and led to a positive net benefit. For the larger aneurysms (4.5-5.4 cm), increasing surveillance intervals from 3 to 6 months led to equivalent cost-effectiveness. LIMITATIONS: There were no clear reasons why the growth rates varied substantially between studies. Uniform diagnostic criteria for rupture were not available. The long-term cost-effectiveness results may be susceptible to the modelling assumptions made. CONCLUSIONS: Surveillance intervals of several years are clinically acceptable for men with AAAs in the range 3.0-4.0 cm. Intervals of around 1 year are suitable for 4.0-4.9-cm AAAs, whereas intervals of 6 months would be acceptable for 5.0-5.4-cm AAAs. These intervals are longer than those currently employed in the UK AAA screening programmes. Lengthening surveillance intervals for the smallest aneurysms was also shown to be cost-effective. Future work should focus on optimising surveillance intervals for women, studying whether or not the threshold for surgery should depend on patient characteristics, evaluating the usefulness of surveillance for those with aortic diameters of 2.5-2.9 cm, and developing interventions that may reduce the growth or rupture rates of small AAAs. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Final follow-up of the Multicentre Aneurysm Screening Study (MASS) randomized trial of abdominal aortic aneurysm screening.

BACKGROUND: The long-term effects of abdominal aortic aneurysm (AAA) screening were investigated in extended follow-up from the UK Multicentre Aneurysm Screening Study (MASS) randomized trial. METHODS: A population-based sample of men aged 65-74 years were randomized individually to invitation to ultrasound screening (invited group) or to a control group not offered screening. Patients with an AAA (3·0 cm or larger) detected at screening underwent surveillance and were offered surgery after predefined criteria had been met. Cause-specific mortality data were analysed using Cox regression. RESULTS: Some 67 770 men were enrolled in the study. Over 13 years, there were 224 AAA-related deaths in the invited group and 381 in the control group, a 42 (95 per cent confidence interval 31 to 51) per cent reduction. There was no evidence of effect on other causes of death, but there was an overall reduction in all-cause mortality of 3 (1 to 5) per cent. The degree of benefit seen in earlier years of follow-up was slightly diminished by the occurrence of AAA ruptures in those with an aorta originally screened normal. About half of these ruptures had a baseline aortic diameter in the range 2·5-2·9 cm. It was estimated that 216 men need to be invited to screening to save one death over the next 13 years. CONCLUSION: Screening resulted in a reduction in all-cause mortality, and the benefit in AAA-related mortality continued to accumulate throughout follow-up. REGISTRATION NUMBER: ISRCTN37381646 (http://www.controlled-trials.com).

Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial.

OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of endosonography (followed by surgical staging if endosonography was negative), compared with standard surgical staging alone, in patients with non-small cell lung cancer (NSCLC) who are otherwise candidates for surgery with curative intent. DESIGN: A prospective, international, open-label, randomised controlled study, with a trial-based economic analysis. SETTING: Four centres: Ghent University Hospital, Belgium; Leuven University Hospitals, Belgium; Leiden University Medical Centre, the Netherlands; and Papworth Hospital, UK. INCLUSION CRITERIA: known/suspected NSCLC, with suspected mediastinal lymph node involvement; otherwise eligible for surgery with curative intent; clinically fit for endosonography and surgery; and no evidence of metastatic disease. EXCLUSION CRITERIA: previous lung cancer treatment; concurrent malignancy; uncorrected coagulopathy; and not suitable for surgical staging. INTERVENTIONS: Study patients were randomised to either surgical staging alone (n = 118) or endosonography followed by surgical staging if endosonography was negative (n = 123). Endosonography diagnostic strategy used endoscopic ultrasound-guided fine-needle aspiration combined with endobronchial ultrasound-guided transbronchial needle aspiration, followed by surgical staging if these tests were negative. Patients with no evidence of mediastinal metastases or tumour invasion were referred for surgery with curative intent. If evidence of malignancy was found, patients were referred for chemoradiotherapy. MAIN OUTCOME MEASURES: The main clinical outcomes were sensitivity (positive diagnostic test/nodal involvement during any diagnostic test or thoracotomy) and negative predictive value (NPV) of each diagnostic strategy for the detection of N2/N3 metastases, unnecessary thoracotomy and complication rates. The primary economic outcome was cost-utility of the endosonography strategy compared with surgical staging alone, up to 6 months after randomisation, from a UK NHS perspective. RESULTS: Clinical and resource-use data were available for all 241 patients, and complete utilities were available for 144. Sensitivity for detecting N2/N3 metastases was 79% [41/52; 95% confidence interval (CI) 66% to 88%] for the surgical arm compared with 94% (62/66; 95% CI 85% to 98%) for the endosonography strategy (p = 0.02). Corresponding NPVs were 86% (66/77; 95% CI 76% to 92%) and 93% (57/61; 95% CI 84% to 97%; p = 0.26). There were 21/118 (18%) unnecessary thoracotomies in the surgical arm compared with 9/123 (7%) in the endosonography arm (p = 0.02). Complications occurred in 7/118 (6%) in the surgical arm and 6/123 (5%) in the endosonography arm (p = 0.78): one pneumothorax related to endosonography and 12 complications related to surgical staging. Patients in the endosonography arm had greater EQ-5D (European Quality of Life-5 Dimensions) utility at the end of staging (0.117; 95% CI 0.042 to 0.192; p = 0.003). There were no other significant differences in utility. The main difference in resource use was the number of thoracotomies: 66% patients in the surgical arm compared with 53% in the endosonography arm. Resource use was similar between the groups in all other items. The 6-month cost of the endosonography strategy was £9713 (95% CI £7209 to £13,307) per patient versus £10,459 (£7732 to £13,890) for the surgical arm, mean difference £746 (95% CI -£756 to £2494). The mean difference in quality-adjusted life-year was 0.015 (95% CI -0.023 to 0.052) in favour of endosonography, so this strategy was cheaper and more effective. CONCLUSIONS: Endosonography (followed by surgical staging if negative) had higher sensitivity and NPVs, resulted in fewer unnecessary thoracotomies and better quality of life during staging, and was slightly more effective and less expensive than surgical staging alone. Future work could investigate the need for confirmatory mediastinoscopy following negative endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), the diagnostic accuracy of EUS-FNA or EBUS-TBNA separately and the delivery of both EUS-FNA or EBUS-TBNA by suitably trained chest physicians. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 97311620. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 18. See the HTA programme website for further project information.

Assessment of potential measures in models of progression in Alzheimer disease.

BACKGROUND: In estimating the potential benefits of treatment, it is often necessary to extrapolate beyond clinical trial results using economic modeling. Previous attempts in Alzheimer disease (AD) were primarily based on the Mini-Mental State Examination (MMSE) due to its widespread use. These models were criticized as not accurately reflecting the total impact of the disease, providing untrustworthy estimates of treatment benefit. We compared 3 alternatives to the MMSE with respect to bridging between clinical outcomes needed for regulatory approval and economic and quality of life (QOL) outcomes important to reimbursement agencies. METHODS: The MMSE, Disability Assessment in Dementia (DAD) scale, Clinical Dementia Rating (CDR) scale, and Dependence Scale (DS) were compared in their ability to explain variation in cognitive, functional, and behavioral measures as well as economic and QOL outcomes using univariate (Pearson correlations) and multivariate (linear regression) analyses of data from research sites in the United States and Europe. RESULTS: Subjects with mild to moderate AD (n = 196; mean 75.9 years; 56% female) were evaluated. The DS, DAD, and CDR were moderately correlated with the MMSE (Pearson correlations, range 0.54-0.58) but performed better (higher adjusted R(2)) than the MMSE in explaining variations in subject behavior, QOL, and health status. The DS and DAD performed better in explaining variation in medical costs, caregiver QOL, and caregiver time. CONCLUSIONS: Measures of function (DAD) or dependence on others (DS), or global measures (CDR), appear to be better candidates than the MMSE for modeling AD progression.

Economic evaluation of healthcare safety: which attributes of safety do healthcare professionals consider most important in resource allocation decisions?

INTRODUCTION: There is an increasing need to assess the value of safety improvements to society. Concerns exist, however, as to what extent standard health economic methods appropriately reflect this value because these methods do not typically incorporate the non-health or extra-consequentialist value of avoiding healthcare incidents, which may--for example, be associated with a decreased trust of patients and citizens in healthcare systems and providers. OBJECTIVES: (1) To identify health and non-health attributes of safety from the literature and (2) to prioritise those that are considered most important by healthcare decision-makers and could be included in a subsequent conjoint analysis to determining the relative value of safety interventions and the willingness to pay of decision-makers. METHODS: A literature review and 25 semistructured interviews have been conducted with healthcare decision-makers experienced in safety management, considering a general healthcare, Methicillin-resistant Staphylococcus aureus (MRSA) and sharps injuries context. RESULTS: The literature review showed that in addition to likelihood of an incident and its direct medical and cost consequences, factors such as preventability, dread, controllability and trust in safety devices or systems affect the value of safety and decision-makers' willingness to pay. The interview results consistently indicated that "preventability of healthcare incidents", "health consequences", "financial consequences" and "trust in safety systems/devices" are the most important attributes across all contexts. In addition, context-specific attributes were identified. CONCLUSION: A set of four common and two context-specific attributes, including health and non-health aspects of safety, was identified. The next step is to attaching appropriate levels to these attributes and to incorporate them into a series of case studies among various groups of decision-makers, healthcare professionals, patient groups and the general public.

The economic consequences of non-adherence to lipid-lowering therapy: results from the Anglo-Scandinavian-Cardiac Outcomes Trial.

BACKGROUND: Adherence to lipid-lowering therapy in clinical practice is less than ideal. Analysis of registry data has indicated that this is associated with poor outcomes. The objective of the present analysis was to assess the impact of high adherence to drug (defined as > 80% of days covered), compared with low adherence to drug (< 50% of days covered) in terms of risk of events and long-term economic consequences. DESIGN: Open-label follow up of a randomised placebo-controlled trial in hypertensive patients. METHODS: Cox proportional hazards and Poisson regression models were used to assess the hazard ratio of patients with high adherence compared with low adherence while controlling for cardiovascular risk. A Markov model was used to predict the long-term costs and health outcomes associated with poor adherence during the follow-up period. RESULTS: Both statistical models indicated that high adherence is associated with improved prognosis [Cox model: 0.75; 95% confidence interval (CI): 0.56-0.98, Poisson model hazard ratio: 0.73; 95% CI: 0.58-0.98]. Discounted at 3.5% per year, the Markov model predicts that as a consequence of higher adherence during the follow-up period, costs would be higher (1689 pounds per patient compared with 1323 pounds per patient) because of higher drug costs, but the projected survival and quality-adjusted survival (QALY) would also be longer (10.83 compared with 10.81 life years and 8.13 compared with 8.11 QALYs). CONCLUSION: Given the higher risk of cardiovascular events associated with low adherence shown here, measures to improve adherence are an important part of the prevention of cardiovascular disease.

Clinical and cost-effectiveness analysis of an open label, single-centre, randomised trial of spinal cord stimulation (SCS) versus percutaneous myocardial laser revascularisation (PMR) in patients with refractory angina pectoris: The SPiRiT trial.

BACKGROUND: Patients with refractory angina have significant morbidity. This study aimed to compare two of the treatment options, Spinal Cord Stimulation (SCS) and Percutaneous Myocardial Laser Revascularisation (PMR) in terms of clinical outcomes and cost-effectiveness. METHODS: Eligible patients were randomised to PMR or SCS and followed up for exercise tolerance time (ETT), Canadian Cardiovascular Society (CCS) classification and the quality of life measures SF-36, Seattle Angina Questionnaire and the EuroQoL at 3, 12 and 24 months. Utilities were calculated using the EQ-5D and these and costs were compared between groups. The incremental cost-effectiveness ratio (ICER) per QALY for SCS compared to PMR was also calculated. RESULTS: At 24 months post-randomisation, patients that had SCS and PMR had similar ETT (mean difference 0.05, 95% CI -2.08, 2.18, p = 0.96) and there was no difference in CCS classification or quality of life outcomes. The difference in overall mean costs when comparing SCS to PMR was GBP5,520 (95% CI GBP1,966 to GBP8,613; p < 0.01) and the ICER of using SCS was GBP46,000 per QALY. CONCLUSION: Outcomes after SCS did not differ appreciably from those after PMR, with the former procedure being less cost-effective as currently applied. Larger studies could clarify which patients would most benefit from SCS, potentially increasing cost-effectiveness. TRIAL REGISTRATION: Current Controlled Trials ISRCTN09648950.

Economic evaluation of ASCOT-BPLA: antihypertensive treatment with an amlodipine-based regimen is cost effective compared with an atenolol-based regimen.

OBJECTIVE: To compare the cost effectiveness of an amlodipine-based strategy and an atenolol-based strategy in the treatment of hypertension in the UK and Sweden. DESIGN: A prospective, randomised trial complemented with a Markov model to assess long-term costs and health effects. SETTING: Primary care. PATIENTS: Patients with moderate hypertension and three or more additional risk factors. INTERVENTIONS: Amlodipine 5-10 mg with perindopril 4-8 mg added as needed or atenolol 50-100 mg with bendroflumethiazide 1.25-2.5 mg and potassium added as needed MAIN OUTCOME MEASURES: Cost per cardiovascular event and procedure avoided, and cost per quality-adjusted life-year gained. RESULTS: In the UK, the cost to avoid one cardiovascular event or procedure would be euro18 965, and the cost to gain one quality-adjusted life-year would be euro21 875. The corresponding figures for Sweden were euro13 210 and euro16 856. CONCLUSIONS: Compared with the thresholds applied by NICE and in the Swedish National Board of Health and Welfare's Guidelines for Cardiac Care, an amlodipine-based regimen is cost effective for the treatment of hypertension compared with an atenolol-based regimen in the population studied.

The cost-effectiveness of an early interventional strategy in non-ST-elevation acute coronary syndrome based on the RITA 3 trial.

BACKGROUND: Evidence suggests that an early interventional strategy for patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) can improve health outcomes but also increase costs when compared with a conservative strategy. OBJECTIVE: The aim of this study was to assess the cost-effectiveness of an early interventional strategy in different risk groups from a UK health-service perspective. DESIGN: Decision-analytic model based on randomised clinical trial data. MAIN OUTCOME MEASURES: Costs in UK Sterling at 2003/2004 prices and quality-adjusted life years (QALYs) combined into an incremental cost-effectiveness ratio. METHODS: Data from the third Randomised Intervention Trial of unstable Angina (RITA 3) was employed to estimate rates of cardiovascular death and myocardial infarction, costs and health-related quality of life. Cost-effectiveness was estimated over patients' lifetimes within the decision-analytic model. RESULTS: The mean incremental cost per QALY gained for an early interventional strategy was approximately 55,000 pounds sterling, 22,000 pounds sterling and 12,000 pounds sterling for patients at low, intermediate and high risk, respectively. The early interventional strategy is approximately 1%, 35% and 95% likely to be cost-effective for patients at low, intermediate and high risk, respectively, at a threshold of 20,000 pounds sterling per QALY. The cost-effectiveness of early intervention in low-risk patients is sensitive to assumptions about the duration of the treatment effect. CONCLUSION: An early interventional strategy in patients presenting with NSTE-ACS is likely to be considered cost-effective for patients at high and intermediate risk, but this is less likely to be the case for patients at low risk.

Modelling the long-term cost-effectiveness of endovascular or open repair for abdominal aortic aneurysm.

BACKGROUND: Recent randomized trials have shown that endovascular abdominal aortic aneurysm repair (EVAR) has a 3 per cent aneurysm-related survival benefit in patients fit for open surgery, but it also has uncertain long-term outcomes and higher costs. This study assessed the cost-effectiveness of EVAR. METHODS: A decision model was constructed to estimate the lifetime costs and quality-adjusted life years (QALYs) with EVAR and open repair in men aged 74 years. The model includes the risks of death from aneurysm, other cardiovascular and non-cardiovascular causes, secondary reinterventions and non-fatal cardiovascular events. Data were taken largely from the EVAR trial 1 and supplemented from other sources. RESULTS: Under the base-case (primary) assumptions, EVAR cost 3800 pounds sterling (95 per cent confidence interval (c.i.) 2400 pounds sterling to 5200 pounds sterling) more per patient than open repair but produced fewer lifetime QALYs (mean -0.020 (95 per cent c.i. -0.189 to 0.165)). These results were sensitive to alternative model assumptions. CONCLUSION: EVAR is unlikely to be cost-effective on the basis of existing devices, costs and evidence, but there remains considerable uncertainty.

Cost-effectiveness of functional cardiac testing in the diagnosis and management of coronary artery disease: a randomised controlled trial. The CECaT trial.

OBJECTIVES: To assess the acceptability and feasibility of functional tests as a gateway to angiography for management of coronary artery disease (CAD), the ability of diagnostic strategies to identify patients who should undergo revascularisation, patient outcomes in each diagnostic strategy, and the most cost-effective diagnostic strategy for patients with suspected or known CAD. DESIGN: A rapid systematic review of economic evaluations of alternative diagnostic strategies for CAD was carried out. A pragmatic and generalisable randomised controlled trial was undertaken to assess the use of the functional cardiac tests: angiography (controls); single photon emission computed tomography (SPECT); magnetic resonance imaging (MRI); stress echocardiography. SETTING: The setting was Papworth Hospital NHS Foundation Trust, a tertiary cardiothoracic referral centre. PARTICIPANTS: Patients with suspected or known CAD and an exercise test result that required non-urgent angiography. INTERVENTIONS: Patients were randomised to one of the four initial diagnostic tests. MAIN OUTCOME MEASURES: Eighteen months post-randomisation: exercise time (modified Bruce protocol); cost-effectiveness compared with angiography (diagnosis, treatment and follow-up costs). The aim was to demonstrate equivalence in exercise time between those randomised to functional tests and those randomised to angiography [defined as the confidence interval (CI) for mean difference from angiography within 1 minute]. RESULTS: The 898 patients were randomised to angiography (n = 222), SPECT (n = 224), MRI (n = 226) or stress echo (n = 226). Initial diagnostic tests were completed successfully with unequivocal results for 98% of angiography, 94% of SPECT (p = 0.05), 78% of MRI (p < 0.001) and 90% of stress echocardiography patients (p < 0.001). Some 22% of SPECT patients, 20% of MRI patients and 25% of stress echo patients were not subsequently referred for an angiogram. Positive functional tests were confirmed by positive angiography in 83% of SPECT patients, 89% of MRI patients and 84% of stress echo patients. Negative functional tests were followed by positive angiograms in 31% of SPECT patients, 52% of MRI patients and 48% of stress echo patients tested. The proportions that had coronary artery bypass graft surgery were 10% (angiography), 11% (MRI) and 13% (SPECT and stress echo) and percutaneous coronary intervention 25% (angiography), 18% (SPECT) and 23% (MRI and stress echo). At 18 months, comparing SPECT and stress echo with angiography, a clinically significant difference in total exercise time can be ruled out. The MRI group had significantly shorter mean total exercise time of 35 seconds and the upper limit of the CI was 1.14 minutes less than in the angiography group, so a difference of at least 1 minute cannot be ruled out. At 6 months post-treatment, SPECT and angiography had equivalent mean exercise time. Compared with angiography, the MRI and stress echo groups had significantly shorter mean total exercise time of 37 and 38 seconds, respectively, and the upper limit of both CIs was 1.16 minutes, so a difference of at least 1 minute cannot be ruled out. The differences were mainly attributable to revascularised patients. There were significantly more non-fatal adverse events in the stress echo group, mostly admissions for chest pain, but no significant difference in the number of patients reporting events. Mean (95% CI) total additional costs over 18 months, compared with angiography, were 415 pounds (-310 pounds to 1084 pounds) for SPECT, 426 pounds (-247 pounds to 1088 pounds) for MRI and 821 pounds (10 pounds to 1715 pounds) for stress echocardiography, with very little difference in quality-adjusted life-years (QALYs) amongst the groups (less than 0.04 QALYs over 18 months). Cost-effectiveness was mainly influenced by test costs, clinicians' willingness to trust negative functional tests and by a small number of patients who had a particularly difficult clinical course. CONCLUSIONS: Between 20 and 25% of patients can avoid invasive testing using functional testing as a gateway to angiography, without substantial effects on outcomes. The SPECT strategy was as useful as angiography in identifying patients who should undergo revascularisation and the additional cost was not significant, in fact it would be reduced further by restricting the rest test to patients who have a positive stress test. MRI had the largest number of test failures and, in this study, had the least practical use in screening patients with suspected CAD, although it had similar outcomes to stress echo and is still an evolving technology. Stress echo patients had a 10% test failure rate, significantly shorter total exercise time and time to angina at 6 months post-treatment, and a greater number of adverse events, leading to significantly higher costs. Given the level of skill required for stress echo, it may be best to reserve this test for those who have a contraindication to SPECT and are unable or unwilling to have MRI. Further research, using blinded reassessment of functional test results and angiograms, is required to formally assess diagnostic accuracy. Longer-term cost-effectiveness analysis, and further studies of MRI and new generation computed tomography are also required.

An assessment of the impact of the NHS Health Technology Assessment Programme.

OBJECTIVES: To consider how the impact of the NHS Health Technology Assessment (HTA) Programme should be measured. To determine what models are available and their strengths and weaknesses. To assess the impact of the first 10 years of the NHS HTA programme from its inception in 1993 to June 2003 and to identify the factors associated with HTA research that are making an impact. DATA SOURCES: Main electronic databases from 1990 to June 2005. The documentation of the National Coordinating Centre for Health Technology Assessment (NCCHTA). Questionnaires to eligible researchers. Interviews with lead investigators. Case study documentation. REVIEW METHODS: A literature review of research programmes was carried out, the work of the NCCHTA was reviewed, lead researchers were surveyed and 16 detailed case studies were undertaken. Each case study was written up using the payback framework. A cross-case analysis informed the analysis of factors associated with achieving payback. Each case study was scored for impact before and after the interview to assess the gain in information due to the interview. The draft write-up of each study was checked with each respondent for accuracy and changed if necessary. RESULTS: The literature review identified a highly diverse literature but confirmed that the 'payback' framework pioneered by Buxton and Hanney was the most widely used and most appropriate model available. The review also confirmed that impact on knowledge generation was more easily quantified than that on policy, behaviour or especially health gain. The review of the included studies indicated a higher level of impact on policy than is often assumed to occur. The survey showed that data pertinent to payback exist and can be collected. The completed questionnaires showed that the HTA Programme had considerable impact in terms of publications, dissemination, policy and behaviour. It also showed, as expected, that different parts of the Programme had different impacts. The Technology Assessment Reports (TARs) for the National Institute for Health and Clinical Excellence (NICE) had the clearest impact on policy in the form of NICE guidance. Mean publications per project were 2.93 (1.98 excluding the monographs), above the level reported for other programmes. The case studies revealed the large diversity in the levels and forms of impacts and the ways in which they arise. All the NICE TARs and more than half of the other case studies had some impact on policy making at the national level whether through NICE, the National Screening Committee, the National Service Frameworks, professional bodies or the Department of Health. This underlines the importance of having a customer or 'receptor' body. A few case studies had very considerable impact in terms of knowledge production and in informing national and international policies. In some of these the principal investigator had prior expertise and/or a research record in the topic. The case studies confirmed the questionnaire responses but also showed how some projects led to further research. CONCLUSIONS: This study concluded that the HTA Programme has had considerable impact in terms of knowledge generation and perceived impact on policy and to some extent on practice. This high impact may have resulted partly from the HTA Programme's objectives, in that topics tend to be of relevance to the NHS and have policy customers. The required use of scientific methods, notably systematic reviews and trials, coupled with strict peer reviewing, may have helped projects publish in high-quality peer-reviewed journals. Further research should cover more detailed, comprehensive case studies, as well as enhancement of the 'payback framework'. A project that collated health research impact studies in an ongoing manner and analysed them in a consistent fashion would also be valuable.

How cost-effective is screening for abdominal aortic aneurysms?

OBJECTIVE: To provide reliable estimates of the long-term cost-effectiveness of abdominal aortic aneurysm screening in men. METHODS: A Markov health economic decision model for screening is described and extrapolated to 30 years. The strategy modelled involves a one-off scan at age 65 years, with annual and three-monthly follow-up scans for small and medium aneurysms, respectively. Referral for elective surgery occurs at an aortic diameter of 5.5 cm. Model parameters are estimated from patient-level data from the UK Multi-centre Aneurysm Screening Study. Model structure is validated on this trial's data, and input parameter uncertainty is addressed by probabilistic sensitivity analysis. Costs and life-years gained are obtained for both screening and no systematic screening strategies. RESULTS: Cost-effectiveness improves dramatically when considered over longer timescales. Taking a 30-year perspective, screening for abdominal aortic aneurysms in men is highly cost-effective at 2320 pounds per life-year gained (95% uncertainty interval: 1600 pounds to 4240 pounds). Adjusting life-years for the age-specific health-related quality of life experienced in this population gave a figure of 2970 pounds (95% uncertainty interval: 2030 pounds to 5430 pounds) per quality-adjusted life-year gained. The additional cost of screening the UK male population is estimated to be 19 m pounds per year. CONCLUSIONS: The long-term cost-effectiveness of screening for abdominal aortic aneurysms in men is highly attractive and this evidence provides further support for a national screening programme in the UK.

Cost effectiveness of clinically appropriate decisions on alternative treatments for angina pectoris: prospective observational study.

OBJECTIVE: To assess whether revascularisation that is considered to be clinically appropriate is also cost effective. DESIGN: Prospective observational study comparing cost effectiveness of coronary artery bypass grafting, percutaneous coronary intervention, or medical management within groups of patients rated as appropriate for revascularisation. SETTING: Three tertiary care centres in London. PARTICIPANTS: Consecutive, unselected patients rated as clinically appropriate (using a nine member Delphi panel) to receive coronary artery bypass grafting only (n=815); percutaneous coronary intervention only (n=385); or both revascularisation procedures (n=520). MAIN OUTCOME MEASURE: Cost per quality adjusted life year gained over six year follow-up, calculated with a National Health Service cost perspective and discounted at 3.5%/year. RESULTS: Coronary artery bypass grafting cost 22,000 pounds sterling (33,000 euros; $43,000) per quality adjusted life year gained compared with percutaneous coronary intervention among patients appropriate for coronary artery bypass grafting only (59% probability of being cost effective at a cost effectiveness threshold of 30,000 pounds sterling per quality adjusted life year) and 19,000 pounds sterling per quality adjusted life year gained compared with medical management among those appropriate for both types of revascularisation (probability of being cost effective 63%). In none of the three appropriateness groups was percutaneous coronary intervention cost effective at a threshold of 30,000 pounds sterling per quality adjusted life year. Among patients rated appropriate for percutaneous coronary intervention only, the cost per quality adjusted life year gained for percutaneous coronary intervention compared with medical management was 47,000, pounds sterling exceeding usual cost effectiveness thresholds; in these patients, medical management was most likely to be cost effective (probability 54%). CONCLUSIONS: Among patients judged clinically appropriate for coronary revascularisation, coronary artery bypass grafting seemed cost effective but percutaneous coronary intervention did not. Cost effectiveness analysis based on observational data suggests that the clinical benefit of percutaneous coronary intervention may not be sufficient to justify its cost.

Evaluation of the ventricular assist device programme in the UK.

OBJECTIVES: To summarise the relevant clinical effectiveness and cost-effectiveness literature, to collect data on survival, transplantation rates, health-related quality of life (HRQoL) and resource use for ventricular assist device (VAD) and non-VAD transplant candidates in the UK, and to construct cost-effectiveness and cost-utility models of VADs in a UK context. Also to investigate the factors that drive costs and survival. DESIGN: A comprehensive systematic review was carried out. Data were collected from April 2002 to December 2004, with follow-up to March 2005. Cost-effectiveness and cost-utility models of VAD devices were developed based on UK activity and outcomes collected from April 2002 to March 2005. SETTING: National Specialist Commissioning Advisory Group funded VAD implantation was carried out at the Freeman, Harefield and Papworth transplant centres in the UK. PARTICIPANTS: Seventy patients were implanted with a VAD as a bridge to transplantation between April 2002 and December 2004. Non-VAD-supported transplant candidates (n = 250), listed at the three centres between April 2002 and December 2004, were divided into an inotrope-dependent group (n = 71) and a non-inotrope-dependent group (n = 179). Although patients in the inotrope-dependent group were closest to the VAD group they were less sick. The last group comprised a hypothetical worst case scenario, which assumed that all VAD patients would die in the intensive care unit (ICU) within 1 month without VAD technology. INTERVENTIONS: Patients were included who were implanted with a VAD designed for circulatory support for more than 30 days, with intention to bridge to transplantation. A multistate model of VAD and transplant activity was constructed; this was populated by data from the UK. MAIN OUTCOME MEASURES: Survival from VAD implant or from transplant listing for non-VAD patients to 31 March 2005. Serious adverse events and quality of life measures were used. Cognitive functioning was also assessed. Utility weights were derived from EuroQoL responses to estimate quality-adjusted life-years (QALYs). Incremental cost-effectiveness ratios (ICERs) were defined as the additional cost of VADs divided by additional QALYs. Time-horizons were 3 years, 10 years and the lifetime of the patients. RESULTS: Of 70 VAD patients, 30 (43%) died pretransplant, 31 (44%) underwent transplantation, and four (6%) recovered and had the VAD removed. Five patients (7%) were still supported for median of 279 days at the end of March 2005. Successful bridge-to-transplantation/recovery rates were consistent with published rates. Survival from VAD implantation was 74% at 30 days and 52% at 12 months. There were 320 non-fatal adverse events in 62 patients during 300 months of VAD support, mostly in the first month after implantation. Commonly observed events were bleeding, infection and respiratory dysfunction. Twenty-nine (41%) patients were discharged from hospital with a VAD. The 1-year survival post-transplantation was 84%. For the inotrope-dependent and non-inotrope-dependent transplant candidates, death rates while listed were 10% and 8% and the median waiting times were 16 and 87 days, respectively. For transplant recipients, 1-year survival was 85% and 84%, respectively. Both VAD and non-VAD patients demonstrated similar significant improvements in their New York Heart Association class after transplantation. All patients had poor EQ-5D pretransplantation; after transplantation the groups had similar EQ-5D of 0.76 irrespective of time after surgery. HRQoL was poor in the first month for VAD patients but better for those who waited longer in all groups. VAD patients reported more problems with sleep and rest and with ambulation in the first month. Symptom scores were similar in all groups pretransplant. After transplantation all groups showed a marked and similar improvement in physical and psychosocial function. Mean VAD implant cost, including device, was pound 63,830, with costs of VAD support for survivors of pound 21,696 in month 1 and pound 11,312 in month 2. Main cost drivers were device itself, staffing, ICU stay, hospital stay and events such as bleeding, stroke and infection. For the base case, extrapolating over the lifetime of the patients the mean cost for a VAD patient was pound 173,841, with mean survival of 5.63 years and mean QALYs of 3.27. Corresponding costs for inotrope-dependent patients were pound 130,905, with mean survival 8.62 years and mean QALYs 4.99. Since inotrope-dependent patients had lower costs and higher QALYs than VAD patients, this group is said to be dominant. Non-inotrope-dependent transplant candidates had similar survival rates to those on inotropes but lower costs, also dominant. Compared with the worst case scenario the mean lifetime ICER for VADs was pound 49,384 per QALY. In a range of sensitivity analyses this ranged from pound 35,121 if the device cost was zero to pound 49,384. Since neither inotrope-dependent transplant candidates nor the worst case scenario were considered fair controls the assumption was investigated that, without VAD technology, there would be a mixture of these situations. For mixtures considered the ICER for VADs ranged from pound 79,212 per QALY to the non-VAD group being both cheaper and more effective. CONCLUSIONS: There are insufficient data from either published studies or the current study to construct a fair comparison group for VADs. Overall survival of 52% is an excellent clinical achievement for those young patients with rapidly failing hearts. However, if the worst case scenario were plausible, and one could reliably extrapolate results to the lifetime of the patients, VADs would not be cost-effective at traditional thresholds. Further randomised controlled trials are required, using current second generation devices or subsequent devices and conducted in the UK.

A review of the evidence on the effects and costs of implantable cardioverter defibrillator therapy in different patient groups, and modelling of cost-effectiveness and cost-utility for these groups in a UK context.

OBJECTIVES: To update the systematic review evidence on the effectiveness, health-related quality of life (HRQoL) and cost-effectiveness of implantable cardioverter defibrillators (ICDs); compilation of new data on the service provision in the UK; and on the clinical characteristics, survival, quality of life and costs of ICD patients in the UK, and a new cost-effectiveness model using both international RCT and UK-specific data. DATA SOURCES: Electronic databases searched from November 1999 to March 2003, this was supplemented by a systematic review of research published during 2003-5. Survey data. REVIEW METHODS: Studies were selected and assessed. A survey of ICD centres was carried out. Basic data were obtained from two major implanting centres including 535 patients (approximately 10% of overall UK activity) implanted between 1991 and 2002, and retrieval of fuller data, on patient characteristics, management and resource use, from patient notes for a sample of 426 patients was attempted. A cross-sectional survey collected HRQoL data (using the Nottingham Health Profile, Short Form 36, Hospital Anxiety and Depression questionnaire, EuroQoL 5 Dimensions and disease-specific questions) on a sample of 229 patients. A Markov model combined UK patient data with data from published randomised controlled trials (RCTs) to estimate incremental costs per life-year or quality-adjusted life-year (QALY) gained. RESULTS: None of the economic analyses in the studies found could be directly applied to the UK. The multiple sources of routine data available (including the national ICD database) provide an imperfect picture of the need for and use of ICDs. Implantation rates have been rising to a rate of around 20 per million population. Mean age is increasing and most ICDs are implanted into men aged 45-74 years. There is significant geographical variation. A survey of 41 UK centres provided additional evidence, particularly of variation in level of activity and resourcing. Most detailed data were obtained for 380 patients (89%). The postal survey produced a 73% response rate. Demographic characteristics of these patients were similar to ICD recipients in the UK as a whole and patients included in secondary prevention RCTs. Mean actuarial survival at 1, 3 and 5 years was 92%, 86% and 71%, respectively. Patient age at implantation and functional status significantly affected survival. Levels of most of the HRQoL measures were lower than for a UK general population. There was no evidence of a change with time from implantation. Patients who had suffered ICD shocks had significantly poorer HRQoL. Most patients nevertheless expressed a high level of satisfaction with ICD therapy. Mean initial costs of implantation showed little variation between centres (23,300 pounds versus 22,100 pounds) or between earlier and more recent implants. There appeared to be greater variation between patients presenting along different pathways. Postdischarge costs (tests, medications and follow-up consultations) and costs of additional hospitalisations were also calculated. Using the Markov model it was found that over a 20-year horizon, mean discounted incremental costs were 70,900 pounds (35,000-142,400 pounds). Mean discounted gain was 1.24 years (0.29-2.32) or 0.93 QALYs. Cost-effectiveness was most favourable for men aged over 70 years with a left ventricular ejection fraction (LVEF) below 35%. If the treatment effect were to continue, then the cost per life-year over a lifetime might fall to around 32,000 pounds. Five RCTs of ICDs, a meta-analysis and, a cost-effectiveness analysis of ICDs used in primary prevention, and a meta-analysis of ICDs in patients with non-ischaemic cardiomyopathy have been published recently. These trials provide confirmation of survival benefit of ICDs used in primary prevention in both ischaemic and non-ischaemic cardiomyopathy patients. Costs per QALY ranged from US$34,000 in older trials to controls being both less expensive and more effective (CABG Patch, DINAMIT). More recent trials estimated cost per QALY between $50,300 and $70,200. The inconsistency in evidence for a HRQoL benefit has not been resolved and further work on risk stratification is necessary. CONCLUSIONS: The evidence of short- to medium-term patient benefit from ICDs is strong but cost-effectiveness modelling indicates that the extent of that benefit is probably not sufficient to make the technology cost-effective as used currently in the UK. One reason is the high rates of postimplantation hospitalisation. Better patient targeting and efforts to reduce the need for such hospitalisation may improve cost-effectiveness. Further cost-effectiveness modelling, underpinned by an improved ICD database with reliable long-term follow-up, is required. The absence of a robust measure of the incidence of sudden cardiac death is noted and this may be an area where further organisational changes with improved data collection would help.

Identifying the impact of diabetes research.

AIMS: Assessment of the impact of health research is a growing but problematic field. We examined how a combination of approaches might together inform assessment of the impact of a body of diabetes research published in 1981 and help identify factors behind success. METHODS: Three broad approaches were applied to the work of one team leader of acknowledged influence. Standard bibliographic analysis was complemented by a second approach which categorized the importance of the primary publications to the papers citing them, in four domains. In parallel, a third approach involved qualitative assessment using surveys, critical pathway analysis by, and interviews of, co-authors and external experts. Extending the approach incorporated key additional publications from other years. RESULTS: In 1981, the team leader published 29 papers. Citations to these 29 first generation papers varied from 1 to 76 and resulted in 799 second generation papers. Citations to these produced 12 891 third generation papers. Analysis of second generation papers suggested the cited first generation paper was thought to be of considerable or essential significance in only 9% of cases. While much research made little impact, qualitative analysis included a wealth of information, sometimes missed by standard bibliographic techniques, on where the identified research influenced important streams of clinical development. Analysis covered major research studies (such as the Diabetes Control and Complications Trial), insulin pump therapy, and career development of co-authors. CONCLUSIONS: Understanding the impact of research requires multiple approaches. With refinement, these techniques could be employed more widely and potentially could inform research policy.